The episode starts with two men and a janitor in a lab. They are discussing the new vaccine for the recent epidemic. One of them complains that it's too soon, no one has even seen the vaccine yet. The janitor lifts his head up and says that he has. They ask him who the hell are you. With a smile, the janitor replies that he is running the experiment, and proceeds to stab the first man with a syringe in the neck. He then backhands the other man and sends him sprawling, telling him to relax, he's part of it too. The janitor unlocks the electronic door, steps out, locks it, and destroys the lock. The second man panics and bangs at the door, shouting at the janitor. Behind him, the first man rises. Too late, the second man turns around, and the first man attacks him. In the background, the test animals start screaming. The janitor looks on, observing, while the second man is killed offscreen. We see blood splatter against the door. "Well, it looks like it works" the janitors says and leaves.

Dean and Sam encounter Crowley while on the trail of Pestilence. Both brothers are angry at Crowley for giving them the Colt which did not work on Lucifer. Crowley mentions that he's being hunted down by his fellow demons and tells the brothers that he knows where the last two rings can be found. He directs them to Brady, the demon handler for the Four Horsemen of the Apocalypse. However, Crowley will only show the way if Sam does not go with them.

Later, Sam and Bobby have an argument over Sam intending to trick Lucifer back into Hell by letting the Devil possess him. Dean meets Brady, the demon-possessed CEO of a pharmaceutical company, who is under Pestilence's orders. Dean tries to trick Brady with a proposition but the demon does not buy it, intending to just kill Dean. However, Crowley gets the drop on Brady and knocks him unconscious. Dean is warned by Crowley that Sam and Brady have a history; Brady is in fact Sam's classmate from college. The Handler possessed Brady since sophomore year, and deliberately introduced Jessica to Sam and then killed her to put Azazel's plans into motion. Sam is furious and wants to kill Brady but Dean stops him. While Crowley is away, Sam traps Dean in the bathroom as he plans to kill Brady. Brady goads Sam into killing him but Sam manages to calm himself and leave. Crowley returns after killing a nest of demons and making it look as though Brady joined his side.

However, Crowley is tracked down by a hellhound. Crowley escapes, leaving Dean, Sam and Brady in the hideout. While Dean attempts to fight off the hellhound, Crowley returns with his own hound against the other hound. After the four of them escape, Brady gives up the location for Pestilence. Dean then allows Sam to finish Brady off. Later, Crowley appears to Bobby and tells him he will reveal Death's location in exchange for his soul.

Pestilence only appears in a flashback at the beginning of the show and Brady communicates with him in a bowl of blood similar to the one the demon that possessed Meg Masters used to communicate with Azazel.

The episode title is the shortened form of the full idiom, 'better the devil you know than the devil you don't'. It means that it is often better to deal with someone or something you are familiar with and know, even if they are not ideal, than take a risk with an unknown person or thing. In this case, Crowley is the devil that Sam and Dean know.

In the very beginning of the episode (after the recap), a poster for Herpexia, the medicine for genital herpes that the Winchesters are forced to do a commercial for in Changing Channels can be seen, hinting that Niveus Pharmaceuticals is its creator.